Abstract
Inhibitory oligonucleotide (IN-ODN) structure-function relationships: species and backbone differences (131.19)
The Journal of immunology (1950), Vol.178(1_Supplement), pp.S241-S241
04/01/2007
DOI: 10.4049/jimmunol.178.Supp.131.19
Abstract
Abstract The recognition of CpG motifs in bacterial DNA by Toll-like Receptor (TLR9) is a key function of the innate immune system, announcing the presence of an infection. We have previously developed synthetic oligonucleotide (ODN) inhibitory of TLR9 function with phosphorothioate (S) backbones conforming to the sequence n CC n not C not C nn GGG nnnn where n is any base. Here we show that these sequence requirements generate IN-ODN when the backbone is phosphodiester (O) also. In general, whereas stimulatory O-ODN are 2 logs less potent than their S-backbone congeners IN-ODN are 3 logs less potent. Changes in the critical bases diminish activity with either backbone; however, when the backbone is S, such changes diminish activity of stimulators much less, and inhibitors much more, than if the backbone is O. Certain end truncations enhance activity and even the minimal sequence CCTGGAGGG retains substantial inhibitory activity. Human-mouse relative activity comparisons tend to be similar between critical base variants, but may differ substantially between end truncation variants. HEK cells transfected with mouse or human TLR9 and an NFkB binding luciferase promoter respond to much lower concentrations of IN-ODN than do primary cells of either species. The neutral sequences with S backbones developed for mouse cells are also neutral with O backbones and with human cells. Supported by AI04737405 from NIH
Details
- Title: Subtitle
- Inhibitory oligonucleotide (IN-ODN) structure-function relationships: species and backbone differences (131.19)
- Creators
- Robert F. AshmanAdam GoekenPetar Lenert
- Resource Type
- Abstract
- Publication Details
- The Journal of immunology (1950), Vol.178(1_Supplement), pp.S241-S241
- DOI
- 10.4049/jimmunol.178.Supp.131.19
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Language
- English
- Date published
- 04/01/2007
- Academic Unit
- Internal Medicine; Immunology; Pathology
- Record Identifier
- 9984362674002771
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